Article with biocompatible coating

ABSTRACT

A coating composition is provided comprising hyaluronic acid or a salt thereof and a blocked polyisocyanate in a solvent comprising water. A method is provided for preparing the coating on a substrate comprising forming a coating mixture of hyaluronic acid or a salt thereof and a blocked polyisocyanate in a solvent comprising water; applying the coating mixture to the substrate; and curing the coating.

This application is a divisional of application Ser. No. 09/708,472,filed on Nov. 9, 2000, now U.S. Pat. No. 6,387,450 B1, which is adivisional of application Ser. No. 09/163,240, filed Sep. 30, 1998, nowU.S. Pat. No. 6,160,032.

FIELD OF THE INVENTION

This invention relates to a lubricious, biocompatible, biomimeticcoating composition, which may be applied to a substrate in one step,comprising hyaluronic acid or a salt thereof, a blocked polyisocyanate,and a solvent, particularly water. The invention also relates to amethod for producing the lubricious, biocompatible, biomimetic coating.

BACKGROUND OF THE INVENTION

It has long been known that hydrophilic coatings with low friction(coefficient of friction of 0.3 or less) are useful for a variety ofmedical devices such as catheters, catheter introducers and the like.When low friction surfaces are used, the devices, upon introduction intothe body, slide easily within arteries, veins, cannula and otherpassageways and body orifices. There have been a wide variety of methodsused to provide the surfaces desired. In some cases the material of thecatheter or medical device is formed of a material having inherentlygood anti-friction properties, such as poly(tetrafluoroethylene) orother plastics. However, in many cases the selection of materials doesnot provide the properties desired in conjunction with other desirableproperties for the particular medical device.

Prior art hydrophilic coatings typically rely on a two step, two coatingprocess, usually involving a primer coat of isocyanate orisocyanate/polymer blend which is dried, followed by a second coatcontaining at least one hydrophilic polymer such as polyvinylpyrrolidone or poly(ethylene oxide). The two coatings, one superimposedon the other, are then baked to effect a cure. This forms aninterpolymer complex or a network including the hydrophilic polymer.

Prior patents have suggested applying solutions of polyvinylpyrrolidonewith isocyanate and/or polyurethane in multi-step operations. Thesecoatings often lack good durability. For example, U.S. Pat. No.4,585,666 issued to Lambert discloses medical devices having hydrophiliccoatings formed from an isocyanate layer overcoated with apolyvinylpyrrolidone layer. However, the multistep procedure makes itdifficult to tailor the properties and values of the final coatings.

U.S. Pat. No. 5,356,433, Rowland et al., describes a two step method forpreparing metal surfaces of medical devices with enhancedbiocompatability properties. The method includes covalently linking anorganosilane compound having amine reactive sites with the metallicsurface of the medical device. A biologically active agent is covalentlylinked to the organosilane compound.

U.S. Pat. No. 5,607,475, Cahalan et al., discloses a two step method forpreparing a metal or glass surface of a medical device with improvedbiocompatibility. The method includes applying to the surface of amedical device a silane compound having a pendant vinyl functionalitysuch that the silane adheres to the surface. A graft polymer is thenformed on the surface with vinylsilane such that the pendant vinylfunctionality of the vinylsilane is incorporated into the graft polymerby covalent bonding with the polymer. Biomolecules are then covalentlybonded to the graft polymer.

U.S. Pat. No. 5,037,677, Halpern et al., describes a two step method ofinterlaminar grafting of coatings upon an object, such as a plasticmedical device, in order to bond sodium hyaluronate to the surface ofthe object. The method includes coating the object with an anchor coatcontaining an acrylic polymer having a grafting functionality in asolvent. The grafting functionality may be an isocyanate group. Theobject is then coated with an aqueous solution containing sodiumhyaluronate. The coatings are heated and the grafting functionality inthe anchor coat reacts with the sodium hyaluronate to form covalentbonds resulting in interlaminar grafting. The isocyanate groups,however, easily react with atmospheric moisture thereby becoming lessavailable or unavailable for reaction with the sodium hyaluronateresulting in a poor coating.

There are several disadvantages to the two step process. First, theexact ratio of primer material to the hydrophilic polymer is difficultto control, as it depends on the amounts of primer and hydrophilicpolymer which happen to be deposited by the wet film during therespective coating steps. Second, the primer may begin to redissolve inthe second coating solution, causing some loss of primer and furtherresulting in difficulty in controlling the primer/hydrophilic polymerratio. Third, since the hydrophilic polymer is not covalently bonded tothe substrate, it may bond to other materials in the area, leading thecoating to lose its desired properties. Fourth, additional facilities,time, and cost are needed for coating with a two step process, ascompared to a one step process.

The present invention provides a coating having hyaluronic acid whichmay be applied in a single step, alleviates the need for a primer orcoupling agent, and can be applied on various substrates, including, butnot limited to, metals and plastics.

Hyaluronic acid is a biopolymer which is present in the human body inbody fluids, joints, and mucous membranes. The biological functions ofhyaluronic acid include protection, lubrication and separation of cells,regulation of transport of molecules and cell metabolites, andmaintenance of the structural integrity of connective tissues and fluidretention intercellular matrix.

SUMMARY OF THE INVENTION

The present invention provides a coating composition comprisinghyaluronic acid or a salt thereof and a blocked polyisocyanate in asolvent comprising water.

According to another embodiment of the present invention, an article isprovided comprising a substrate to which a coating compositioncomprising hyaluronic acid or a salt thereof and a blockedpolyisocyanate in a solvent comprising water, is applied.

According to yet another embodiment of the invention, a method ofpreparing a coating on a substrate to be coated comprises forming amixture of hyaluronic acid or a salt thereof and a blockedpolyisocyanate in a solvent comprising water; applying the mixture tothe substrate; and curing the mixture on the substrate to form thecoating.

These and other features and objects of the invention are more fullyappreciated from the following detailed description of a preferredembodiment of the invention.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

According to the present invention, a coating is formed from thereaction on a substrate to be coated of a mixture comprising hyaluronicacid or a salt thereof and a blocked polyisocyanate in a solvent. Thesolvent comprises water and, optionally, a water miscible cosolvent. Theresulting coating is highly lubricious and thromboresistant.

The coating composition is prepared by weighing the appropriatequantities of hyaluronic acid or salt thereof, blocked polyisocyanate,and solvent into an appropriate mixing vessel. Additional solvents maybe added to adjust the viscosity of the mixture. Solids contents in arange of from about 0.1 to about 25% and viscosities in the range of 50cps to 500 cps are preferred. This solution is mixed well and thenapplied to an appropriate substrate, such as catheter tubes, medicaltubing introducers, polymer coated medical wires, stents, guide wires,and dilatation balloons, by conventional coating application methods.Such methods include, but are not limited to, dipping, spraying, wiping,painting, and the like.

After applying the coating solution, the solvent is preferably allowedto evaporate from the coated substrate, such as by exposure to ambientconditions for at least 5 minutes.

The coating is subsequently cured. The cure time, temperature, andhumidity vary with the choice of hyaluronic acid or salt thereof,blocked polyisocyanate, solvent, and the composition of the substrate.The ratio of ingredients in the coating mixture also affects thephysical properties of the overall coating. The amount of sodiumhyaluronate controls the lubricity of the coating. The amount of blockedpolyisocyanate controls the flexibility of the coating.

Cure temperatures may range from about 120° C. to about 150° C. Curetimes may range from about 5 minutes to about 1 hour, depending upon thecure temperature and the reactivity of the hyaluronic acid or saltthereof and blocked polyisocyanate. In all cases the cure conditionsshould be non-deleterious to the underlying substrate.

After the coating is cured, it is preferable to rinse or soak thecoating in water to remove any uncomplexed polymers. Generally, a briefrinse of 10-15 seconds is sufficient, however, a longer rinse or soak isacceptable since the coating is cured and forms a stable gel when incontact with water. After rinsing, the coating may be dried either atambient conditions, or at elevated temperatures.

After the coating is formed, the coating can imbibe water from anaqueous solution prior to introduction to the body to become lubricious.Alternatively, the coating can imbibe water from body fluids, even ifnot exposed to water prior to introduction into the body. The coatingretains its lubricating properties upon rehydration even when dried andremoistened repeatedly. If the coating is to be used for items such ascatheters, introducer tubes and the like, the materials selected shouldbe compatible with and non-toxic to the body. Since hyaluronic acid is abiopolymer, it is biocompatible. The coating may be applied to varioussubstrates, including, but not limited to, metals, ceramics, organicmaterials including plastics, and glass.

The coating may be applied to metal substrates such as the stainlesssteel used for guide wires and other devices, nitinol which is an alloyof nickel and titanium, and tantalum.

The organic substrates which may be coated with the coatings of thisinvention include, but are not limited to, polyether block amide,polyethylene terephthalate, polyetherurethane, polyesterurethane, otherpolyurethanes, natural rubber, rubber latex, synthetic rubbers,polyester-polyether copolymers, and polycarbonates. Some of thesematerials are available under various trademarks such as Pebax™available from Atochem, Inc. of Glen Rock, N.J.; Mylar™ available fromE.I. duPont deNemours and Co. of Wilmington, Del.; Texin™ 985A fromMobay Chemical Corporation of Pittsburgh, Pa.; Pellethane™ availablefrom Dow Chemical of Midland, Mich.; and Lexan available from GeneralElectric Company of Pittsfield, Mass.

The hyaluronic acid preferably has an average molecular weight of fromabout 70,000 to about 6 million daltons, more preferably from about300,000 to 2 million daltons, and most preferably from about 500,000 toabout 1 million daltons. Preferably, the amount of hyaluronic acidranges from about 0.1 to about 5 percent, by weight, based upon loottotal weight of coating composition. More preferably, the amount ofhyaluronic acid ranges from about 0.1 to about 2 percent, by weight, andmost preferably from about 0.25 to about 1 percent, by weight. Belowabout 0.2 percent hyaluronic acid, the coating is not very lubricious.Above 1 percent hyaluronic acid, the coating is too lubricious for mostapplications. As the average molecular weight increases, the amount ofhyaluronic acid may be decreased.

A preferred salt of hyaluronic acid is sodium hyaluronate. Other usablesalts include potassium hyaluronate. Derivatives of hyaluronic acid,such as sulfated or acetylated hyaluronic acid may also be used.

Preferably, the blocked polyisocyanate is hexamethylene diisocyanate andis dissolved in N-methyl-2-pyrrolidone; the amount of blockedpolyisocyanate ranges from about 0.1 to about 5 percent, by weight,based upon 100% total weight of coating composition. More preferably,the amount of blocked polyisocyanate ranges from about 0.1 to about 2percent, by weight, and most preferably from about 0.5 to about 2percent by weight. Blocked polyisocyanates are generally reactionproducts of isocyanates with certain active hydrogen compounds such thatthe addition product has only limited thermal stability. For example,blocked polyisocyanates may be prepared by reacting polyisocyanates withphenol, m-cresol, diethyl malonate, ethyl acetoacetate, ore-caprolactam.

The ratio by weight of hyaluronic acid to blocked polyisocyanatepreferably ranges from about 0.5:1 to about 2:1.

The solvent employed should be non-reactive with the hyaluronic acid orblocked polyisocyanate and is a solvent for all the components. Thesolvent comprises water and optionally, a water miscible cosolvent.Suitable cosolvents include, but are not limited to tetrahydrofuran,acetone, acetonitrile, and dimethylsulfoxide. Preferably, the cosolventis tetrahydrofuran.

Wetting agents may be added to the coating solution to improvewettability to hydrophobic surfaces. Wetting agents include, but are notlimited to, fluorinated alkyl esters, such as Fluorad™ FC-430 availablefrom 3M Corp., and octylphenol ethylene oxide condensates, such asTriton™ X-100 available from Union Carbide. A preferred concentration ofwetting agent in the coating solution is from about 0.01 to about 0.2%by weight based upon 100% solids in the coating solution.

Drugs may be added to the coating mixture; the result is a drug elutingcoating.

Viscosity and flow control agents may be added to the coating mixture toadjust the viscosity and thixotropy of the mixture to a desired level.The viscosity is such that the coating can be formed on the substrate atthe desired thickness. Viscosities of from about 50 cps to about 500 cpsmay be used although higher or lower viscosities may be useful incertain instances. Viscosity control agents include, but are not limitedto, fumed silica, cellulose acetate butyrate, and ethyl acrylate/2-ethylhexyl acrylate copolymer. Flow control agents are preferably present inamounts of from about 0.05 to about 5 percent, by weight, based upon100% total weight of coating composition and more preferably in amountsof from about 0.1 to about 2 percent. Flow control agents includeacrylic copolymers, including Modaflow™ available from Monsanto.

Antioxidants may be added to the coating mixture to improve oxidativestability of the cured coatings. Antioxidants include, but are notlimited to, tris(3,5-di-t-butyl-4-hydroxy benzyl)isocyanurate,2,2′-methylenebis(4-methyl-6-t-butyl phenol),1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene, butylhydroxy toluene, octadecyl 3.5 di-t-butyl-4-hydroxyhydrocinnamate, 4,4methylenebis(2,6-di-butylphenol), p,p′-dioctyl diphenylamine, and1,1,3-tris-(2-methyl-4-hydroxy-5-t-butylphenyl)butane. When used,antioxidants are preferably present in amounts from 0.01 to 1 percent,by weight, based upon 100% total weight of coating composition.

Conventional pigments may be added to the coating mixture to impartcolor or radiopacity, or to improve the appearance of the coatings.

Air release agents or defoamers which are optionally included in thecoating solution include, but are not limited to, polydimethylsiloxanes, 2,4,7,9-tetramethyl-5-decyn-4,7-diol, 2-ethylhexyl alcohol,and n-beta-aminoethyl-gamma-amino-propyl-trimethoxysilane. Air releaseagents are preferably added in amounts from 0.005 to 0.5 percent, byweight, based upon 100% total weight of coating composition.

The following non-limiting examples are meant to be illustrativeembodiments of the present invention. In each of the examples, themolecular weight of the hyaluronic acid which formed the sodium salt wasapproximately 720,000 daltons.

EXAMPLE 1

A diluted solution of hexamethylene diisocyanate was prepared bycombining and mixing thoroughly 50.18 g. hexamethylene diisocyanate inN-methyl-2-pyrrolidone, available as Bayhydur™ BL116 from BayerCorporation, and 46.25 g. distilled water.

The coating solution was prepared by combining, in order, the followingingredients and mixing them thoroughly:

(a) 0.19 g. of the diluted hexamethylene diisocyanate solution;

(b) 0.2 g. of sodium hyaluronate available from Life Core Medical; and

(c) 20.29 g. distilled water.

The coating solution was applied to coupons A, B, and C. Coupons A, B,and C were made of stainless steel 316. Prior to coating, each couponwas washed with hexane for 15 minutes in an ultrasonic bath, rinsed withdistilled water, washed with isopropyl alcohol for 15 minutes in anultrasonic bath, rinsed with distilled water, washed with sodiumhydroxide for 15 minutes, and rinsed with distilled water.

The coupons were coated by dipping them into the coating solution. Thecoupons were lowered into the coating solution at a speed of 110 in/minand held in the coating solution for 2 minutes. Coupons A, B, and C werewithdrawn from the coating solution at speeds of 110, 42, and 10 in/min,respectively. The greater the withdrawal speed, the thicker the coatingon the coupon. The coupons were then placed in an oven at 140° C. for 20minutes to effect curing of the coating. The coating contained 1% sodiumhyaluronate and 0.5% hexamethylene diisocyanate.

A toluidine blue solution was prepared by mixing 0.5 g. of toluidineblue and 98 g. of water. Each coupon was dipped into the toluidine bluesolution for 30 seconds to 1 minute. Then the coupon was rubbed withfinger pressure 10 to 20 times.

The rubbed coupon was again dipped in the toluidine blue solution andthen observed for cracks and missing spots in the coating. A uniformcoating causes the toluidine blue to adhere to the coating. In spotswhere the coating has been rubbed off, the toluidine blue does notadhere to the coupon. A “good stain” refers to a uniform coating afterrubbing.

The lubricity of a coating was determined by comparing it to an uncoatedcoupon and a coupon coated with Bayhydur™ but without hyaluronic acid.

Coupon A, B, and C exhibited good stain and good slip. Excess toluidineblue easily came off coupons B and c.

Similar results are obtained when hyaluronic acid is employed in placeof the sodium salt.

EXAMPLE 2

A coating solution was prepared by combining in order the followingingredients and mixing them thoroughly:

(a) 19.2 g. distilled water;

(b) 0.2 g. of sodium hyaluronate available from Life Core Medical; and

(c) 0.2 g. of the diluted hexamethylene diisocyanate solution describedin Example 1.

Coated coupons D, E, and F were prepared with this coating solution andtested as described in Example 1. The coating contained 1% sodiumhyaluronate and 0.5% hexamethylene diisocyanate.

Coupon D exhibited dark stain and good slip. Coupons E and F exhibitedgood stain and good slip. Excess toluidine blue easily came off couponsD, E, and F.

Similar results are obtained when the potassium salt of hyaluronic acidis employed in place of the sodium salt.

EXAMPLE 3

A coating solution was prepared by combining in order the followingingredients and mixing them thoroughly:

(a) 0.42 g. of the diluted hexamethylene diisocyanate solution describedin Example 1;

(b) 0.04 g. of sodium hyaluronate available from Life Core Medical; and

(c) 19.98 g. distilled water.

Coupons G, H, and I were prepared with this coating solution and testedas described in Example 1. The coating contained 0.2% sodium hyaluronateand 1.1% hexamethylene diisocyanate.

Coupon G exhibited good stain but was not slippery. Coupons H and Iexhibited fair stain but were not slippery since the ratio of sodiumhyaluronate to hexamethylene diisocyanate was 2:11, which is too low.

EXAMPLE 4

A diluted solution of sodium hyaluronate was prepared by combining andmixing thoroughly 0.2 g. sodium hyaluronate available from Life CoreMedical and 99.8 g. distilled water.

A diluted solution of hexamethylene diisocyanate was prepared bycombining and mixing thoroughly 10 g. hexamethylene diisocyanate inN-methyl-2-pyrrolidone, available as Bayhydur™ BL116 from BayerCorporation, and 10 g. tetrahydrofuran.

The coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 20 g. of the diluted sodium hyaluronate solution;

(b) 0.1 g. of the diluted hexamethylene diisocyanate solution; and

(c) 10 g. tetrahydrofuran.

Coupons J, K, and L were coated by dipping them into the coatingsolution. The coupons were lowered into the coating at a speed of 110in/min and held in the coating solution for 2 minutes. The coupons werewithdrawn from the coating solution at a speed of 42in/min. The coatingcontains 0.13% sodium hyaluronate and 0.17% hexamethylene diisocyanate.

Coupons J, K, and L exhibited good stain and slight slip due to the lowconcentration of sodium hyaluronate in the coating.

EXAMPLE 5

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 20 g. of the diluted sodium hyaluronate solution described inExample 4;

(b) 0.2 g. of the diluted hexamethylene diisocyanate solution describedin Example 4; and

(c) 10 g. tetrahydrofuran.

Coupons M, N, and O were prepared with this coating solution and testedas described in Example 4. The coating contains 0.13% sodium hyaluronateand 0.33% hexamethylene diisocyanate.

Coupons M, N, and O exhibited good stain and slight slip due to the lowconcentration of sodium hyaluronate in the coating.

EXAMPLE 6

A diluted solution of hexamethylene diisocyanate was prepared bycombining and mixing thoroughly 50 g. hexamethylene diisocyanate inN-methyl-2-pyrrolidone, available as Bayhydur™ BL116 from BayerCorporation, and 46 g. distilled water.

The coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 20 g. of the diluted sodium hyaluronate solution described inExample 4; and

(b) 0.2 g. of the diluted hexamethylene diisocyanate solution describedin Example 4.

Coupons P and Q were prepared with this coating solution and tested asdescribed in Example 1.

Coupons P and Q exhibited some voids in the coating and slight slip dueto the low concentration of sodium hyaluronate in the coating.

EXAMPLES 7-9 AND 11-17 AND COMPARATIVE EXAMPLE 10

For Examples 7-9 and 11-17 and Comparative Example 10, the followingsolutions were prepared:

A water-tetrahydrofuran solution was prepared by combining and mixingthoroughly 106.0 g. distilled water and 100.34 g. tetrahyhydrofuran.

A 1% sodium hyaluronate solution was prepared by combining and mixingthoroughly 1 g. sodium hyaluronate available from Life Core Medical, 49g. distilled water and 50 g. tetrahydrofuran.

A 0.5% sodium hyaluronate solution was prepared by combining and mixingthoroughly 39.99 g. of the 1% sodium hyaluronate solution and 40.09 g.of the water-tetrahydrofuran solution.

A 0.25% sodium hyaluronate solution was prepared by combining and mixingthoroughly 0.120 g. sodium hyaluronate available from Life Core Medicaland 49.10 g. distilled water.

A diluted solution of hexamethylene diisocyanate was prepared bycombining and mixing thoroughly 5.03 g. hexamethylene diisocyanate inN-methyl-2-pyrrolidone, available as Bayhydur™ BL116 from BayerCorporation, and 5.06 g. of the water-tetrahydrofuran solution.

EXAMPLE 7

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 20.01 g. of the 0.5% sodium hyaluronate solution; and

(b) 0.12 g. of the diluted hexamethylene diisocyanate to solution.

Coupons R, S, and T were washed with hexane for 15 minutes in anultrasonic bath, rinsed with distilled water, washed with isopropylalcohol for 15 minutes in an ultrasonic bath, rinsed with distilledwater, washed with sodium hydroxide for 15 minutes, rinsed withdistilled water, and dried off.

The coupons were coated by dipping them into the coating solution. Eachcoupon was lowered into the coating solution at a speed of 110 in/minand held in the coating solution for 2 minutes. Each coupon waswithdrawn from the coating solution at a speed of 42 in/min. and was airdried for 20 minutes and then placed in an oven at 140° C. for 20minutes to effect curing of the coating.

A toluidine blue solution was prepared by mixing 0.5 g. of toluidineblue and 98 g. of water.

Coupon R was dipped in the toluidine blue solution for approximately 1minute and was then rubbed with finger pressure 10 to 20 times. Therubbed coupon was dipped in the toluidine blue solution and thenobserved for cracks and missing spots in the coating. A uniform coatingcauses the toluidine blue to adhere to the coating. Coupon S was alsorub tested but without the toluidine blue solution. After 3 days in aflusher, coupon T was rub tested, followed by staining with toluidineblue solution to determine the durability of the coating. The flusherwas a system having a continuous flow of saline at 37° C.

The lubricity of the coating was determined by comparing it to anuncoated coupon and a coupon coated with Bayhydur™, but withouthyaluronic acid.

Coupon R exhibited a thick coating and good stain, but was not slippery.Coupon S was slippery. Coupon T was slippery and exhibited good stainindicating a durable coating.

EXAMPLE 8

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 19.58 g. of the 0.5% sodium hyaluronate solution; and

(b) 0.20 g. of the diluted hexamethylene diisocyanate solution.

Three coupons were prepared with this coating solution and tested asdescribed in Example 7. A fourth coupon was prepared with this coatingsolution and rub tested with the toluidine blue solution after 8 days ina flusher to determine the durability of the coating. The fourth couponwas also tested for lubricity as described in Example 7.

The first coupon exhibited a thick coating and good stain but was notslippery; the second coupon was slippery; the third coupon exhibited adurable coating and was very slippery after three days in a flusher; andthe fourth coupon also exhibited a durable coating and was slipperyafter eight days in a flusher.

EXAMPLE 9

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 19.98 g. of the 0.5% sodium hyaluronate solution; and

(b) 0.41 g. of the diluted hexamethylene diisocyanate solution.

Three coupons were prepared with this coating solution and tested asdescribed in Example 7.

The first coupon exhibited a thick coating and good stain, but was notslippery; the second coupon was slippery; and the third coupon exhibiteda durable coating and was very slippery after three days in a flusher.

COMPARATIVE EXAMPLE 10

The coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 15.03 g. of hexamethylene diisocyanate in N-methyl-2-pyrrolidoneavailable as Bayhydur™ BL116 from Bayer Corporation; and

(b) 15.07 g. of the tetrahydrofuran-water solution.

Two coupons were prepared with this coating solution and tested asdescribed in Example 7. The second coupon was tested without thetoluidine blue solution.

The first coupon exhibited no stain and was not slippery. The secondcoupon was not slippery.

EXAMPLE 11

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 10.00 g. of the coating solution of Example 7; and

(b) 10.03 g. of the water-tetrahydrofuran solution.

A coupon prepared with this coating solution and tested in a flusher for3 days as described in Example 7 exhibited good stain and was slippery.

EXAMPLE 12

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 10.01 g. of the coating solution of Example 8; and

(b) 10.02 g. of the water-tetrahydrofuran solution.

A coupon prepared with this coating solution and tested in a flusher for3 days as described in Example 7 exhibited good stain and was slippery.

EXAMPLE 13

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 10.07 g. of the coating solution of Example 9; and

(b) 10.04 g. of the water-tetrahydrofuran solution.

A coupon prepared with this coating solution and tested in a flusher for3 days as described in Example 7 exhibited good stain and was slippery.

EXAMPLE 14

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 20.08 g. of the 0.25% sodium hyaluronate solution; and

(b) 0.05 g. of the diluted hexamethylene diisocyanate solution.

A coupon prepared with this coating solution was tested for lubricityand durability, as described in Example 7; it exhibited good stain andwas slippery. The coating contained 0.25% sodium hyaluronate.

EXAMPLE 15

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 19.98 g. of the 0.25% sodium hyaluronate solution; and

(b) 0.1 g. of the diluted hexamethylene diisocyanate solution.

A coupon prepared with this coating solution was tested for lubricityand durability, as described in Example 7; it exhibited good stain andwas slippery. The coating contained 0.25% sodium hyaluronate.

EXAMPLE 16

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 10 g. of the coating solution of Example 14; and

(b) 10 g. of the tetrahydrofuran-water solution.

A coupon prepared with this coating solution, rub tested, and tested forlubricity as described in Example 7 exhibited good stain and was onlyslightly slippery. The coating contained 0.125% sodium hyaluronate.

EXAMPLE 17

A coating solution was prepared by combining the following ingredientsand mixing them thoroughly:

(a) 10 g. of the coating solution of Example 15; and

(b) 10 g. of the tetrahydrofuran-water solution.

A coupon prepared with this coating solution, rub tested, and tested forlubricity as described in Example 7 exhibited good stain and was onlyslightly slippery. The coating contained 0.125% sodium hyaluronate.

While a preferred embodiment of the present invention has beendescribed, it should be understood that various changes, adaptations andmodifications may be made therein without departing from the spirit ofthe invention and the scope of the appended claims.

What is claimed is:
 1. An article comprising a substrate and a coating,wherein said coating is the product of a cured composition comprising:(a) hyaluronic acid or a salt thereof; (b) a blocked polyisocyanate; and(c) water.
 2. The article according to claim 1, wherein said substrateis selected from the group consisting of metal, plastic, and glass. 3.The article according to claim 1, wherein said blocked polyisocyanate ishexamethylene diisocyanate.
 4. The article according to claim 1, whereinsaid solvent further comprises a water miscible solvent.
 5. The articleaccording to claim 4, wherein said water miscible solvent is selectedfrom the group consisting of tetrahydrofuran, acetone, acetonitrile, anddimethyl sulfoxide.
 6. An article according to claim 1, wherein thehyaluronic acid content of said composition is from about 0.1 to about5% by weight based upon 100% total weight of said coating composition.7. An article according to claim 6, wherein the hyaluronic acid contentof said composition is from about 0.1 to about 2% by weight based upon100% total weight of said coating composition.
 8. An article accordingto claim 7, wherein the hyaluronic acid content of said composition isfrom about 0.25 to about 1% by weight based upon 100% total weight ofsaid coating composition.
 9. An article according to claim 1, whereinthe blocked polyisocyanate content of said composition is from about 0.1to about 5% by weight based upon 100% total weight of said coatingcomposition.
 10. An article according to claims 9, wherein the blockedpolyisocyanate content of said composition is from about 0.1 to about 2%by weight based upon 100% total weight of said coating composition. 11.An article according to claim 10, wherein the blocked polyisocyanatecontent of said composition is from about 0.5 to about 2% by weightbased upon 100% total weight of said coating composition.
 12. An articleaccording to claim 1, which is selected from the group consisting of acatheter, a catheter introducer, a wire, a stent and a dilatationballoon.
 13. An article according to claim 12, wherein the wire is aguide wire.
 14. An article according to claim 13, wherein the hyaluronicacid content of said composition is from about 0.1 to about 5% by weightbased upon 100% total weight of said coating composition.
 15. An articleaccording to claim 13, wherein the blocked polyisocyanate content ofsaid composition is from about 0.1 to about 5% by weight based upon 100%total weight of said coating composition.
 16. An article according toclaim 12, which is a catheter.
 17. An article according to claim 16,wherein the hyaluronic acid content of said composition is from about0.1 to about 5% by weight based upon 100% total weight of said coatingcomposition.
 18. An article according to claim 16, wherein the blockedpolyisocyanate content of said composition is from about 0.1 to about 5%by weight based upon 100% total weight of said coating composition. 19.An article according to claim 12, which is a stent.
 20. An articleaccording to claim 19, wherein the hyaluronic acid content of saidcomposition is from about 0.1 to about 5% by weight based upon 100%total weight of said coating composition.
 21. An article according toclaim 19, wherein the blocked polyisocyanate content of said compositionis from about 0.1 to about 5% by weight based upon 100% total weight ofsaid coating composition.